Overall: UCLA SPORE in Brain Cancer SUMMARY/ABSTRACT The objectives of the UCLA SPORE in Brain Cancer are to contribute significantly to progress in the diagnosis, prognosis, and treatment of brain cancer. These goals will be accomplished through multiple and diverse research projects involving mechanistic pre-clinical work and innovative clinical studies, with a particular focus on developing novel strategies to overcome the problem of treatment resistance. The broad, long-term objectives and aims of our brain cancer SPORE are as follows: 1) to investigate mechanisms of immune evasion following active immunotherapy, and develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment; 2) to elucidate the alterations in metabolism associated with targeted therapy resistance, and exploit these metabolic vulnerabilities to induce intrinsic apoptosis of tumor cells; 3) to explore the concept of radiation-induced phenotype conversion of non-tumorigenic cells to glioblastoma-initiating cells as a mechanism for radiation resistance, and test new therapeutics to block such glioma stem cell conversion; and 4) to investigate the pathways of resistance to IDH inhibitors, and utilize novel epigenetic pathways to sensitize IDH-mutant gliomas to treatment. In order to achieve these translational research goals of our program, we propose four main projects involving: 1) active immunotherapy combined with immune checkpoint modulation for glioblastoma; 2) targeting metabolic vulnerabilities in glioblastoma cells; 3) inhibition of radiation-induced phenotype conversion to glioma-initiating stem cells; and 4) novel epigenetic treatment of IDH mutant gliomas. These translational research projects will be supported by shared resource cores in administration, biospecimen/pathology, neuroimaging, and biostatistics/bioinformatics/data management. Our program will also be responsive to SPORE themes by incorporating Developmental Research and Career Enhancement Programs in order to foster new approaches for assessing and treating brain cancer. Our diverse array of novel projects and state-of-the-art cores will likely make a significant impact on brain cancer patient care. Each project has been developed jointly by teams of basic and clinical researchers working together in a trans-disciplinary manner to address the most vexing problem in brain cancer ? the development of treatment resistance. All four projects are highly translational and will reach human endpoints within the context of this SPORE grant period.